rs76726076

Variant names:

• chrX-153863865-G-A
• rs76726076
• NM_001278116.2:c.3457+18C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-153863865-G-A
• chrX-153863865-G-C
• chrX-153863865-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001278116.2(L1CAM):​c.3457+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,210,593 control chromosomes in the GnomAD database, including 17 homozygotes. There are 690 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., 108 hem., cov: 24)
  • Exomes 𝑓: 0.0016 (16 hom. 582 hem.)
• Consequence: L1CAM NM_001278116.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.32

Genes affected

L1CAM (HGNC:6470): (L1 cell adhesion molecule) The protein encoded by this gene is an axonal glycoprotein belonging to the immunoglobulin supergene family. The ectodomain, consisting of several immunoglobulin-like domains and fibronectin-like repeats (type III), is linked via a single transmembrane sequence to a conserved cytoplasmic domain. This cell adhesion molecule plays an important role in nervous system development, including neuronal migration and differentiation. Mutations in the gene cause X-linked neurological syndromes known as CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia and hydrocephalus). Alternative splicing of this gene results in multiple transcript variants, some of which include an alternate exon that is considered to be specific to neurons. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-153863865-G-A is Benign according to our data. Variant chrX-153863865-G-A is described in ClinVar as [Benign]. Clinvar id is 458214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00186 (211/113145) while in subpopulation EAS AF= 0.0167 (60/3586). AF 95% confidence interval is 0.0133. There are 1 homozygotes in gnomad4. There are 108 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 108 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.3457+18C>T		intron_variant	Intron 26 of 28	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.3457+18C>T		intron_variant	Intron 25 of 27		NP_000416.1
L1CAM	NM_024003.3	c.3457+18C>T		intron_variant	Intron 25 of 26		NP_076493.1
L1CAM	NM_001143963.2	c.3442+18C>T		intron_variant	Intron 24 of 25		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.3457+18C>T		intron_variant	Intron 26 of 28	5	NM_001278116.2	ENSP00000359077.1

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 211 AN: 113093 Hom.: 1 Cov.: 24 AF XY: 0.00307 AC XY: 108 AN XY: 35223

Gnomad AFR AF: 0.0000321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000649

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.0167

Gnomad SAS AF: 0.000357

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000506

Gnomad OTH AF: 0.000656

GnomAD3 exomes AF: 0.00315 AC: 574 AN: 182254 Hom.: 1 AF XY: 0.00304 AC XY: 204 AN XY: 67010

Gnomad AFR exome AF: 0.0000764

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.0168

Gnomad SAS exome AF: 0.000263

Gnomad FIN exome AF: 0.0155

Gnomad NFE exome AF: 0.000788

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00161 AC: 1772 AN: 1097448 Hom.: 16 Cov.: 32 AF XY: 0.00160 AC XY: 582 AN XY: 362862

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.000170

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.0263

Gnomad4 SAS exome AF: 0.000388

Gnomad4 FIN exome AF: 0.0160

Gnomad4 NFE exome AF: 0.000208

Gnomad4 OTH exome AF: 0.00221

GnomAD4 genome AF: 0.00186 AC: 211 AN: 113145 Hom.: 1 Cov.: 24 AF XY: 0.00306 AC XY: 108 AN XY: 35285

Gnomad4 AFR AF: 0.0000320

Gnomad4 AMR AF: 0.000648

Gnomad4 ASJ AF: 0.00113

Gnomad4 EAS AF: 0.0167

Gnomad4 SAS AF: 0.000358

Gnomad4 FIN AF: 0.0176

Gnomad4 NFE AF: 0.000506

Gnomad4 OTH AF: 0.000648

Alfa AF: 0.00113 Hom.: 9

Bravo AF: 0.000752

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Benign:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.47
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs76726076; hg19: chrX-153129320;